Moxetumomab Pasudotox-tdfk (Lumoxiti(TM)) and Either Rituximab (Rituxan(R)) or Ruxience for Relapsed Hairy Cell Leukemia

• ClinicalTrials.gov Identifier: NCT03805932
• Recruitment Status: Active, not recruiting
• First Posted: January 16, 2019
• Last Update Posted: April 13, 2023
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Study Description

Brief Summary:

Background:

Hairy cell leukemia (HCL) is a rare, slow-growing blood cancer in which the bone marrow makes too many of certain white blood cells. The antibody Rituximab/Ruxience binds to a protein in cancerous white blood cells and is often used to treat HCL. Researchers want to see if combining it with the drug Moxetumomab pasudotox-tdfk (also called Lumoxiti) can fight HCL better.

Objective:

To test the safety of Moxetumomab pasudotox taken with Rituximab/Ruxience for people with HCL or HCL variant.

Eligibility:

People age 18 years and older with HCL or HCL variant that has not responded to standard therapy

Design:

Participants will be screened with:

Medical history

Physical exam

Blood, heart, and urine tests

Test of blood oxygen levels

Review of bone marrow. This can be from previous test results or a new sample.

Scans

Exercise test

Participants will get the study drugs in up to 8 cycles. A cycle will last about 28 days.

The study drugs will be given through a plastic tube in a vein.

In the first week of cycle 1, participants will have:

1 visit to get Rituximab or Ruxience for 7.5 hours

3 visits to get Lumoxiti for 30 minutes per infusion

In the first week of cycles 2-8, participants will have:

1. visit to get Rituximab/Ruxience for 2-4 hours and Lumoxiti for 30 minutes
2. visits to get Lumoxiti for 30 minutes per infusion

Participants will be asked to drink lots of water and take aspirin during the cycles. They will get drugs to minimize allergic reactions.

Participants will repeat screening tests at visits throughout the cycles and 1 follow-up visit. They may have an eye exam.

...

Condition or disease	Intervention/treatment	Phase
Hairy Cell Leukemia	Drug: Moxetumomab Pasudotox-tdfk; Biological: Rituximab; Biological: Ruxience	Phase 1

Detailed Description:

Background:

• Hairy cell leukemia (HCL) is an indolent CD22+ B-cell leukemia comprising 2% of all leukemias, or approximately 1200 of the 62,130 new cases of leukemia/year in the US. HCL variant (HCLv), also CD22+, is 10-20% as common as HCL, but more common in the relapsed/refractory population due to its poor prognosis and response to standard purine analog chemotherapy. HCLv cells are CD25-negative and wild type for BRAF, so HCLv patients are not candidates for BRAF inhibitors. CD25+ classic-appearing HCL-cells that express unmutated IGHV4-34 are wild-type for BRAF, remain brightly CD22 positive, and confer a poor prognosis when treated with chemotherapy.
• Moxetumomab pasudotox-tdfk is a recombinant immunotoxin containing a variable domain (Fv) fragment of an anti-CD22 monoclonal antibody and truncated Pseudomonas exotoxin, which kills CD22+ cells by binding to CD22 via the Fv fragment, and induction of apoptotic cell death catalytic inhibition of protein synthesis in the cytosol.
• Moxetumomab pasudotox-tdfk in phase 1 testing demonstrated a high complete response (CR) rate in patients with chemoresistant HCL, without dose-limiting toxicity (DLT), but with reversible grade 2 hemolytic uremic syndrome (HUS) not requiring plasmapheresis.
• Moxetumomab pasudotox-tdfk completed multicenter phase 3 testing in 80 patients, meeting its CR endpoint, with 8.8% incidence each of capillary leak syndrome (CLS, grade 3-4 2.5%), and HUS (grade 3-4 6.3%), both reversible.
• Moxetumomab pasudotox-tdfk is the only known non-chemotherapy-containing regimen for HCL which can consistently eradicate minimal residual disease (MRD), and this is associated with prolonged CR durations. Recently, US Food and Drug Administration (FDA) has accepted the Biologics License Application (BLA) for moxetumomab pasudotox-tdfk as the treatment of adult patients with HCL.
• Patients who did not achieve CR, or CR with MRD, often made neutralizing antibodies to the bacterial-based toxin, and/or had collections of HCL cells not completely eradicated by Moxetumomab pasudotox-tdfk. Both issues may be addressed by the addition of anti-CD20 monoclonal antibody (Mab) rituximab or Ruxience to Moxetumomab pasudotox-tdfk.

Objective:

-To determine the safety and toxicity of Moxetumomab pasudotox-tdfk and rituximab/Ruxience used at the planned dose level, in patients with HCL and HCLv.

Eligibility:

• HCL or HCLv with at least 1 prior purine analog, and, for HCL patients with >=2-years 1 month response, at least 1 other therapy.
• Need for treatment, either 1) ANC <1/nL, 2) Hgb <10g/dL, 3) Plt <100/nL, 4) symptomatic splenomegaly, or enlarging HCL mass > 2cm in short axis
• Serum creatinine < 1.5 mg/dL, or creatinine clearance greater than or equal to 60 mL/min by Cockcroft-Gault equation, where creatinine clearance = (140-age)(kg weight)/(72 x Creatinine).
• No uncontrolled infection or cardiopulmonary dysfunction

Design:

• Phase I trial, two arm, non-randomized, dose escalation

• Administration:

  • Patients 1-13: Moxetumomab pasudotox-tdfk 30-40 mcg/kg intravenous (iv) over 30 min, Rituximab 375 mg/m^2 iv, 50-400 mg/hr.
  • Patients 14-26: Moxetumomab pasudotox-tdfk 40 mcg/kg intravenous (iv) over 30 min, Ruxience 375 mg/m2 iv, 50-400 mg/hr
  • Rituximab or Ruxience day 1 (begin day -2 on cycle 1), Moxetumomab pasudotox-tdfk days 1, 3, and 5.
  • Patients will receive up 4 cycles past documentation of CR without MRD, maximum 8.
  • To prevent renal toxicity and hypovolemia, patients will be encouraged to drink water gradually, approximately 0.5-1 cup/hour or 6L/day, not going >3 hours without drinking from days 1 to 8 and to keep a hydration diary to record daily fluid consumption.
  • To prevent rituximab/Ruxience toxicity, patients will receive prophylactic dexamethasone orally 0.5- 2 hours before the 1st dose of rituximab, and before subsequent doses until rituximab/Ruxience infusion reactions are not seen. Patients will also receive diphenhydramine, famotidine, and acetaminophen.
  • Dexamethasone 4 mg orally (maximum 2 doses/day) will be given as needed to treat nausea or fever associated with Moxetumomab pasudotox-tdfk, which might prevent adequate water intake

• Statistical design:

  • Up to 26 patients are intended to be treated in the trial. While a total of 26 evaluable patients will be enrolled, the accrual ceiling will be set at 30 to include screen failures and inevaluable patients.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 15 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I Study of Moxetumomab Pasudotox-tdfk (Lumoxiti (TM)) and Either Rituximab (Rituxan (R)) or Ruxience for Relapsed Hairy Cell Leukemia
• Actual Study Start Date: October 3, 2019
• Estimated Primary Completion Date: June 30, 2024
• Estimated Study Completion Date: June 30, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1 - Dose Escalation; Moxetumomab Pasudotox-tdfk + Rituximab	Drug: Moxetumomab Pasudotox-tdfk; Moxetumomab pasudotox-tdfk is administered at 30-40 ug/Kg iv over 30 min given on days 1, 3, 5 of each cycle.; Biological: Rituximab; Rituximab will be administered at 375mg/m^2 iv, 50-400 mg/hr. On cycle 1, Rituximab is given on day -2, on subsequent cycles, Rituximab is given on day 1.
Experimental: 2- Dose Expansion; Moxetumomab Pasudotox-tdfk + Ruxience	Drug: Moxetumomab Pasudotox-tdfk; Moxetumomab pasudotox-tdfk is administered at 30-40 ug/Kg iv over 30 min given on days 1, 3, 5 of each cycle.; Biological: Ruxience; Ruxience will be administered at 375mg/m^2 iv, 50-400 mg/hr. On cycle 1, Ruxience is given on day -2, on subsequent cycles, Ruxience is given on day 1 (Delta)

Outcome Measures

Primary Outcome Measures :

1. safety and toxicity [ Time Frame: 4 weeks ]
   Determine recommended safe dose of moxetumomab pasudotox-tdfk and rituximab/Ruxience.

Secondary Outcome Measures :

1. Response rates [ Time Frame: 1, 2 and 3.5 years after EOT, then every 2 years ]
   Percentage of patients whose cancer shrinks or disappears after treatment
2. MRD-free rates [ Time Frame: 1, 2 and 3.5 years after EOT, then every 2 years ]
   Percentage of patients without minimal residual disease
3. Response duration [ Time Frame: 1, 2 and 3.5 years after EOT, then every 2 years ]
   Time of initial response until documented tumor progression

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

• INCLUSION CRITERIA:
• Diagnosis of HCL or HCLv.
• Treatment required for either 1) Absolute neutrophil count (ANC) <1/nL, 2) Hemoglobin <10g/dL, 3) Platelets<100/nL, 4) symptomatic splenomegaly, or 5) enlarging HCL mass > 2cm in short axis. Patients who have eligible blood counts within 4 weeks from the initiation of study will not be considered ineligible if subsequent blood counts prior to enrollment fluctuate and become ineligible up until the time of enrollment.
• Patients must be Pseudomonas-immunotoxin naive.
• HCL or HCLv with at least 1 prior purine analog, and, for HCL patients with >=2-years 1 month response, at least 1 other therapy. Age greater than or equal to 18 years as the disease under study, HCL/HCLv, has not been reported in children < age 18.
• ECOG performance status less than or equal to2 (Karnofsky greater than or equal to 60%)

• Patients must have adequate organ and marrow function as defined below:

  • Total bilirubin less than or equal to 1.5 mg/dL, unless consistent with Gilbert s (ratio between total and direct bilirubin > 5)
  • AST and ALT less than or equal to 3x upper limit of normal (ULN)
  • Alkaline phosphatase < 2.5 ULN
  • Serum creatinine less than or equal to 1.5 mg/dL or creatinine clearance greater than or equal to 60 mL/min by Cockcroft-Gault equation, where creatinine clearance = (140-age)(Kg weight)/(72 x Creatinine)
  • Serum albumin greater than or equal to 2 g/dL
  • Partial thromboplastin time (PTT) or Prothrombin time (PT)/International Normalized Ratio < 2.5x ULN (If on warfarin, PT/INR < 3.5x ULN; If on any other anticoagulation, Prothrombin time (PT) < 2.5x baseline)
  • Fibrinogen greater than or equal to 0.5 lower limit of normal

• The effects of moxetumomab pasudotox-tdfk and rituximab/Ruxience on the developing human fetus are unknown therefore participants must use effective methods of contraception as directed below.

  • Females of childbearing potential (< 50 years) who are sexually active with a non-sterilized male partner must use a highly effective method of contraception prior to study entry and or the duration of study participation and must agree to continue using such precautions for 12 months after completion of rituximab/Ruxience administration. Contraception after this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Females of childbearing potential are defined as those who are not surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or those who are premenarchal or postmenopausal (defined as 12 months with no menses without an alternative medical cause). A highly effective method of contraception is defined as one that results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly. Not all methods of contraception are highly effective. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
  • Non-sterilized males who are sexually active with a female partner of childbearing potential must use an effective method of contraception from Day 1 until 90 days after receipt of the final dose of investigational product. It is required that a female partner of a male subject also use an effective method of contraception throughout this period.
• Ability of subject to understand and the willingness to sign a written informed consent document.
• Patients must be willing to co-enroll in the investigator s companion protocol 10C-0066 titled Collection of Human Samples to Study Hairy Cell and other Leukemias, and to Develop Recombinant Immunotoxins for Cancer Treatment.

EXCLUSION CRITIERIA:

• Patients who have had chemotherapy, immunotherapy or radiotherapy within 4 weeks or treatment with rituximab/Ruxience within last 3 months prior to initiation of treatment.
• Patients who are receiving any other investigational agents.
• Breastfeeding within the projected duration of the study, starting with the screening visit through 6 months after the last dose of rituximab/Ruxience. Pregnant women are excluded from this study because moxetumomab pasudotox-tdfk and rituximab/Ruxience are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with moxetumomab pasudotox-tdfk and rituximab/Ruxience, breastfeeding should be discontinued if the mother is treated with moxetumomab pasudotox-tdfk and rituximab/Ruxience.
• Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension, uncontrolled pulmonary infection, pulmonary edema or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients with retinal or choroidal detachment.
• Positive for Hepatitis B core antibody or surface antigen unless the patient is on Tenofovir or Entecavir and Hepatitis B Viral deoxyribonucleic acid (DNA) load is <2000 IU/mL
• Active second malignancy requiring treatment other than minor resection of indolent cancers like basal cell and squamous skin cancers.
• Human immunodeficiency virus (HIV)-positive patients unless taking appropriate anti-HIV medications with a CD4 count of > 200. Otherwise, there may be an increased risk of lethal infections when temporarily suppressing normal B-cells.
• History of an allogeneic bone marrow transplant.
• Patients with a history of both thromboembolism and known congenital hypercoagulable conditions.
• Radioimmunotherapy within 2 years prior to enrollment in the study.
• Patients with history of thrombotic microangiopathy or thrombotic microangiopathy /HUS.
• Patients with corrected QT interval (Frederica) elevation > 500 msec (manually over-read by medically qualified person) based on at least two separate 12-lead ECGs.
• Patients on high dose estrogen (defined as > 0.625 mg/day of an estrogen compound).
• Oxygen saturation at rest < 88% measured by pulse oximetry or PaO2 less than or equal to 55 mm Hg.
• Patients with life expectancy of less than 6 months.
• Patients with clinical evidence of disseminated intravascular coagulation (Grade 3-4).
• Patients with < 50% of predicted forced expiratory volume (FEV1) or < 50% of predicted diffusing capacity for carbon monoxide, corrected for hemoglobin concentration and alveolar volume (DLCO). Note: Patients with no prior history of pulmonary illness are not required to have pulmonary function testing (PFT). Forced expiratory volume will be assessed after bronchodilator therapy.

Contacts and Locations

Locations

United States, Maryland

National Institutes of Health Clinical Center

Bethesda, Maryland, United States, 20892

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Robert J Kreitman, M.D.; National Cancer Institute (NCI)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT03805932
• Other Study ID Numbers: 190042; 19-C-0042
• First Posted: January 16, 2019
• Last Update Posted: April 13, 2023
• Last Verified: April 11, 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: .All IPD recorded in the medical record will be shared with intramural investigators upon request.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: Clinical data available during the study and indefinitely.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):

HCL Variant; Recombinant Immunotoxin; Monoclonal Antibody; Targeted Therapy; Biologic Therapy

Additional relevant MeSH terms:

Leukemia; Leukemia, Hairy Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Rituximab; Immunotoxin HA22; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Immunotoxins; Immunoconjugates